JP4889172B2 - Moisture sensitive transdermal formulation - Google Patents
Moisture sensitive transdermal formulation Download PDFInfo
- Publication number
- JP4889172B2 JP4889172B2 JP2001502819A JP2001502819A JP4889172B2 JP 4889172 B2 JP4889172 B2 JP 4889172B2 JP 2001502819 A JP2001502819 A JP 2001502819A JP 2001502819 A JP2001502819 A JP 2001502819A JP 4889172 B2 JP4889172 B2 JP 4889172B2
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- Prior art keywords
- drug
- preparation
- adhesive layer
- permeation control
- storage layer
- Prior art date
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Classifications
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
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Description
技術分野
本発明は、経皮吸収型製剤に関するもので、より具体的には保存時においては透過制御膜が薬物不透過性で、薬物は薬物貯蔵層中で安定に存在し、製剤適用時に皮膚から揮散する水分により透過制御膜が可塑化することにより薬物が粘着剤層に移行し、経皮吸収させうるリザーバー型経皮吸収型製剤に関する。
背景技術
従来の経皮吸収型製剤としては、薬物貯蔵層と薬物の活性化剤を薬物不透過性の膜によって分割し、適用時に使用者が不透過性膜を破壊、破裂させることにより薬物が活性化剤により粘着剤層に移行し経皮吸収させるシステムが報告されている（特開平１−８５９１２）。しかし、この場合使用者が適用時に破壊、破裂させるという作業を要するため、患者のコンプライアンスの低下につながり、また製造方法が煩雑であるという欠点がある。また、粘着剤層中に薬物を含有する貼付剤の場合、薬物が粘着剤層中で不安定な化合物であると徐々に分解、劣化し長期保存性に欠け、薬物の含量低下、ひいては治療効果の低減を招くという問題があった。
発明の開示
本発明は、使用方法及び製造方法が簡便で、更には、薬物が粘着剤層中で不安定な化合物である場合でも、保存時においては薬物の分解、劣化を抑制して薬物が安定に保存され、製剤適用時に薬物が粘着剤層及び皮膚へ移行し経皮吸収させうる経皮吸収型製剤を提供することを目的とする。
本発明者らは、前記課題を解決するために鋭意研究を重ねた結果、支持体、薬物貯蔵層、透過制御膜、粘着剤層及び剥離材からなる経皮吸収型製剤であって、前記透過制御膜が該製剤の適用時に皮膚から揮散する水分により可塑化されることを特徴とする経皮吸収型製剤が、当該課題を解決することを見出し本発明を完成させるに至った。
即ち、本発明は以下の発明を包含する。
（１）支持体、薬物貯蔵層、透過制御膜、粘着剤層及び剥離材からなる経皮吸収型製剤であって、前記透過制御膜が該製剤の適用時に皮膚から揮散する水分により可塑化されることを特徴とする経皮吸収型製剤。
（２）前記透過制御膜が水溶性ポリマーである前記（１）記載の経皮吸収型製剤。
（３）前記水溶性ポリマーがポリビニルアルコールである前記（２）記載の経皮吸収型製剤。
（４）薬物貯蔵層が薬物又は薬物及び賦形剤で形成される前記（１）記載の経皮吸収型製剤。
（５）前記薬物が水溶性である前記（４）記載の経皮吸収型製剤。
（６）前記賦形剤が水崩壊性物質である前記（４）記載の経皮吸収型製剤。
（７）前記支持体の透湿度が４０℃、２４時間で１００ｇ／ｍ２以下である前記（１）記載の経皮吸収型製剤。
（８）前記粘着剤の透湿度が４０℃、２４時間で１００ｇ／ｍ２以上である前記（１）記載の経皮吸収型製剤。
（９）治療用薬物がニコランジル、塩酸ドパミン又は塩酸エペリゾンである前記（１）記載の経皮吸収型製剤。
以下、本発明を詳細に説明する。
本発明の経皮吸収型製剤は、支持体、薬物貯蔵層、透過制御膜、粘着剤層及び剥離材からなる経皮吸収型製剤であって、前記透過制御膜が該製剤の適用時に皮膚から揮散する水分により可塑化されることを特徴とする。
「可塑化」とは「外力により物質が塑性変形、塑性流動を起こしやすくなるようにすること」であり、この場合、水分を吸収して透過制御膜が塑性流動を起こし、水分によって活性化された薬物が透過制御膜に浸透、溶解、分散又は拡散することである。
本発明の経皮吸収型製剤において透過制御膜は、薬物貯蔵層と粘着剤層との間に位置し、製剤適用時に皮膚から揮散される水分により可塑化されることが必要で、これにより薬物、又は、薬物及び賦形剤は透過制御膜に浸透、溶解、分散又は拡散し粘着剤層に移行し薬物が経皮吸収される。透過制御膜としては、皮膚から揮散する水分により可塑化され、製剤適用時に薬物が透過するものであればその成分は特に限定されない。このような透過制御膜としては水溶性ポリマーが挙げられるが、好ましくはポリビニルアルコール、ポリビニルピロリドン等の合成高分子、可溶性デンプン、デキストリン、セルロース、メチルセルロース、カルボキシメチルセルロース等の多糖類、コーンスターチ、アルギン酸ナトリウム、アラビアゴム、ゼラチン、プルラン等の天然高分子、ポリリン酸ナトリウム、水ガラス等の無機高分子であり、特にポリビニルアルコールが好ましい。
本発明の経皮吸収型製剤において薬物貯蔵層は、薬物、又は薬物及び賦形剤により形成される。
賦形剤としては、一般に使用されているものであれば特に限定されないが、好ましくは水崩壊性物質が挙げられる。ここでいう「水崩壊性物質」とは「薬物貯蔵層作製時には賦形剤として、製剤適用時には水分の存在下崩壊剤として機能する物質」のことである。このような水崩壊性物質としては、例えば、ブドウ糖、乳糖、蔗糖、デンプン、可溶性デンプン、メチルセルロース等の糖類、ポリエチレングリコール類、ポリソルベート類等が挙げられる。
薬物貯蔵層に用いられる治療用薬物としては、経皮吸収されるものであれば特に限定されないが、好ましくはニコランジル、塩酸ドパミン又は塩酸エペリゾン等のアミン系治療用薬物である。
更に、治療用薬物としては、非ステロイド系抗炎症薬、ステロイド系抗炎症薬、抗不整脈薬、抗腫瘍薬、睡眠薬、向精神薬、局所麻酔薬、強心薬、抗生物質、抗結核薬、鎮痛薬、筋肉緩和剤、抗喘息薬、抗コリン作動薬、血管拡張薬、抗高血圧薬、抗ヒスタミン薬、コリン作動薬、アンジオテンシン転換酵素阻害薬等が挙げられる。
本発明の経皮吸収型製剤において使用される治療用薬物は、皮膚から揮散する水分により可塑化された透過制御膜に浸透、溶解、分散又は拡散することが必要である。
薬物貯蔵層中には、必要に応じて、カオリン、タルク、ベントナイト、酸化チタン、炭酸水素カルシウム、硫酸アルミニウム、無水ケイ酸、酸化亜鉛、シリカ、アルミナ等の添加剤；ＢＨＴ、ＢＨＡ、グアヤコールエステル、ノルジヒドログアヤレチック酸等の酸化防止剤；クロタミトン、ベンジルアルコール、エタノール、セバシン酸ジエチル、ミリスチン酸イソプロピル等の吸収促進剤等を添加してもよい。
薬物貯蔵層を本発明の経皮吸収型製剤中に保持するために、薬物貯蔵層の上部又は外部を支持体で覆う必要がある。
本発明の経皮吸収型製剤において支持体としては、薬物不透過性、不透湿性のものであれば特に限定されないが、４０℃、２４時間後の透湿度（ＪＩＳ Ｚ０２０８「防湿包装材料の透湿度試験方法（カップ法）」に準ずる）が１００ｇ／ｍ２以下のものが好ましい。このような支持体としては、例えば、ポリエチレンテレフタレート、ポリエチレン、ポリプロピレン等のフィルムやシート、これらの２種以上を用いた積層シート、更に前記フィルムやシートと不織布又は織布との積層シート等が挙げられる。
本発明の経皮吸収型製剤において粘着剤としては、皮膚貼付可能で、透湿性であればその成分は特に限定されないが、４０℃、２４時間後の透湿度が１００ｇ／ｍ２以上のものが好ましい。このような粘着剤としては、例えば、アクリル系粘着剤、ゴム系粘着剤又はシリコーン系粘着剤等が挙げられる。粘着剤層には、上記粘着剤のほか、必要に応じて、ロジン系樹脂、テルペン系樹脂、芳香族炭化水素樹脂、脂肪族炭化水素樹脂、石油樹脂、エステルガム、油脂性フェノール樹脂等の粘着付与剤、ミリスチン酸イソプロピル、オレイン酸オレイル、ポリブテン、イソポリブテン、流動パラフィン、スクワレン、シリコーン油、オリーブ油、大豆油、ナタネ油、ヤシ油、牛脂等の軟化剤；カオリン、タルク、ベントナイト、酸化チタン、炭酸水素カルシウム、硫酸アルミニウム、無水ケイ酸、酸化亜鉛、シリカ、アルミナ等の添加剤；ＢＨＴ、ＢＨＡ、グアヤコールエステル、ノルジヒドログアヤレチック酸等の酸化防止剤；クロタミトン、ベンジルアルコール、エタノール、セバシン酸ジエチル、ミリスチン酸イソプロピル等の吸収助剤を含有させてもよい。
本発明の経皮吸収型製剤において剥離材としては、柔軟で薬物不透過性のものであれば特に限定されず、例えば、ポリエチレン、ポリエステル等のフィルムに剥離剤としてシリコーン樹脂を塗布したものが挙げられる。
本発明の経皮吸収型製剤の一態様として、図１（Ａ）及び（Ｂ）に示す構造を有するものを例示することができる。
図１（Ａ）及び（Ｂ）中、１は支持体であり、２は薬物貯蔵層であり、３は透過制御膜であり、４は粘着剤層であり、５は剥離材である。
図１に示す経皮吸収型製剤において、支持体１は薬物貯蔵層２の上部又は外部に位置し、薬物貯蔵層２を保持する役割を果たす。透過制御膜３は薬物貯蔵層２の下部に位置し、薬物の粘着剤層４への透過を制御する役割を果たす。粘着剤層４は透過制御膜３の下部に位置し、貼付剤を皮膚に接着させる役割を果たす。貼付剤を使用する際には、粘着剤層４の下部に位置する剥離材（リリースライナー）５を除去し皮膚に貼付する。
薬物貯蔵層２中に含有される薬物は透過制御膜３及び粘着剤層４を通じて経皮吸収される。
本明細書は本願の優先権の基礎である特願平１１−１６５６９３号の明細書に記載される内容を包含する。
発明を実施するための最良の形態
以下、実施例及び比較例により本発明を更に具体的に説明するが、本発明の範囲はこれらの実施例に限定されるものではない。
（実施例１）
アクリル系粘着剤（ＰＥ−３００、日本カーバイド工業製）１００重量部に対し、架橋剤（ＣＫ−１０１、日本カーバイド工業製）４．０重量部を添加し、前記全重量に対する固形重量％が４０重量％となるように酢酸エチルを添加し、ディスパーにて十分に撹拌し均一溶液を調製した。この溶液を厚さ３８μｍのポリエチレンテレフタレートフィルムからなる剥離フィルム上に均一に塗布し、８０℃の乾燥機中にて４分間乾燥させて、塗布量が５０ｇ／ｍ２となるように粘着剤層を形成した。ついで、透過制御膜である厚さ２５μｍのポリビニルアルコールフィルムを粘着剤層上に貼合した。
ニコランジル１０重量部をメタノール９０重量部に溶解させニコランジル濃度が１０％（ｗ／ｗ）となるように調製した。この溶液を厚さ５０μｍのポリエチレンテレフタレートフィルム上に均一に塗布し、６０℃の乾燥機中にて１分間乾燥させ、ニコランジルの含有量が約３００ｍｇ／ｍ２となるように薬物貯蔵層を形成した。
これを先に作製したポリビニルアルコールフィルム、粘着剤層及び剥離材と貼合し、経皮吸収型製剤を作製した。
（実施例２）
実施例１の薬物貯蔵層の作製において、ニコランジルの塗布量を約３００ｍｇ／ｍ２から約６００ｍｇ／ｍ２となるように作製する点を除いて実施例１と同様の操作を行い、経皮吸収型製剤を作製した。
（実施例３）
実施例１の薬物貯蔵層の作製を以下のとおり行った。まず精製水１００重量部に賦形剤として可溶性デンプン４重量部を溶解させ、ついでニコランジル２０重量部を添加し、ここにエタノール３００重量部を加え撹拌した。この液をポリエチレンテレフタレートフィルム上に均一に塗布し、１１０℃の乾燥機中にて３分間乾燥させ薬物貯蔵層とした。この操作を除いて実施例１と同様の操作を行い、ニコランジルの含有量が約３００ｍｇ／ｍ２となるように経皮吸収型製剤を作製した。
（実施例４）
実施例１において使用したニコランジルの代わりに、塩酸エペリゾンを使用する点を除いて実施例１と同様の操作を行い、塩酸エペリゾンの含有量が約３００ｍｇ／ｍ２となるように経皮吸収型製剤を作製した。
（実施例５）
実施例１において使用したニコランジルの代わりに、塩酸ドパミンを使用する点を除いて実施例１と同様の操作を行い、塩酸ドパミンの含有量が約３００ｍｇ／ｍ２となるように経皮吸収型製剤を作製した。
（実施例６）
実施例１の薬物貯蔵層の作製を以下のとおり行った。ニコランジル２０重量部と賦形剤として可溶性デンプン８０重量部を混合、分散させ、これを透過制御膜上に均一に塗布した。この操作を除いて実施例１と同様の操作を行い、ニコランジルの含有量が約３００ｍｇ／ｍ２となるような経皮吸収型製剤を作製した。
（比較例１）
アクリル系粘着剤（ＰＥ−３００、日本カーバイド工業製）１００重量部に対し、架橋剤（ＣＫ−１０１、日本カーバイド工業製）４．０重量部、さらにニコランジルを０．２７重量部添加し、前記全重量に対する固形重量％が４０重量％となるように酢酸エチルを添加し、ディスパーにて十分に撹拌し均一溶液を調製した。この溶液を厚さ３８μｍのポリエチレンテレフタレートフィルムからなる剥離フィルム上に均一に塗布し、８０℃の乾燥機中にて４分間乾燥させて、塗布量が５０ｇ／ｍ２、ニコランジルの含有量が約３００ｍｇ／ｍ２となるように粘着剤層を形成した。ついで、厚さ５０μｍのポリエチレンテレフタレートフィルムを貼合し、経皮吸収型製剤を作製した。
（比較例２）
比較例１において使用したニコランジルの代わりに、塩酸エペリゾンを使用する点を除いて比較例１と同様の操作を行い、塩酸エペリゾンの含有量が約３００ｍｇ／ｍ２となるように経皮吸収型製剤を作製した。
（比較例３）
比較例１において使用したニコランジルの代わりに、塩酸ドパミンを使用する点を除いて比較例１と同様の操作を行い、塩酸ドパミンの含有量が約３００ｍｇ／ｍ２となるように経皮吸収型製剤を作製した。
（試験例１）
実施例１〜６及び比較例１〜３で得られた以下の表１に示す組成を有する経皮吸収型製剤を２５ｍｍ×１５０ｍｍに裁断しアルミニウム包材にて包装し、実施例１〜３、６及び比較例１に関しては２３℃の恒温槽（湿度６５％）にて８週間、実施例４、５比較例２、３に関しては４０℃の恒温槽（ドライ）にて７日間保存し、製剤中の薬物残存量をＨＰＬＣで定量した。経時安定性試験の結果を表２に示す。
実施例１〜３で得た経皮吸収型製剤を使用し、下記の方法により経皮吸収性の評価を行った。
８週令（体重１７０〜１９０ｇ）の雄性ウイスターラットを頚部屠殺した後、腹部皮膚をバリカン及びシェーバーで除毛して摘出した。真皮側の脂肪をハサミで取り除いた後、角質層側に前記実施例１〜３で得た経皮吸収型製剤を貼付し、あらかじめ３７℃に保った縦型拡散セル（セル容積４．０ｍｌ、有効拡散面積０．９５ｃｍ２）に適用し、真皮側にｐＨ７．４等張リン酸緩衝液を適用して透過実験を行った。実験中は真皮側セル中に入れたスターヘッド型撹拌子をマグネティックスターラーにより撹拌した。経時的に一定量のサンプルを採取し、あらかじめ内部標準物質を含有したアセトニトリルに加え、ＨＰＬＣにより透過した薬物を定量した。透過試験開始後１２時間までの累積薬物透過量を図２に示す。図２中、○は実施例１の結果を、□は実施例２の結果を、△は実施例３の結果を表す。
本明細書で引用した全ての刊行物、特許及び特許出願をそのまま参考として本明細書中にとり入れるものとする。
産業上の利用の可能性
本発明によれば、使用方法及び製造方法が簡便で、更には保存時においては薬物の分解・劣化を抑制して薬物は安定に保存され、製剤適用時に薬物が粘着剤層および皮膚へ移行し経皮吸収させうる経皮吸収型製剤を提供することができる。
【図面の簡単な説明】
図１は、本発明の経皮吸収型製剤の断面図である。
なお、図中の番号は次のものを示す。
１… 支持体
２… 薬物貯蔵層
３… 透過制御膜
４… 粘着剤層
５… 剥離材
図２は、本発明の経皮吸収型製剤の経皮吸収性試験の結果を示す図である。TECHNICAL FIELD The present invention relates to a transdermally absorbable preparation, and more specifically, a permeation control membrane is drug-impermeable during storage, and the drug is stably present in the drug reservoir layer, and the skin is applied during formulation application. The present invention relates to a reservoir-type percutaneous absorption preparation that can be percutaneously absorbed by transfer of a drug to an adhesive layer by plasticization of a permeation control film by moisture volatilized from the skin.
Background Art As a conventional transdermal preparation, a drug storage layer and a drug activator are divided by a drug-impermeable film, and the user destroys and ruptures the impermeable film at the time of application. A system for transferring to the adhesive layer by an activator and percutaneously absorbing has been reported (JP-A-1-85912). However, in this case, since the user needs to perform the operation of breaking and rupturing at the time of application, there is a drawback that the compliance of the patient is lowered and the manufacturing method is complicated. In the case of a patch containing a drug in the pressure-sensitive adhesive layer, if the drug is an unstable compound in the pressure-sensitive adhesive layer, it gradually decomposes and deteriorates and lacks long-term storage stability. There was a problem of incurring a reduction in
DISCLOSURE OF THE INVENTION The present invention is simple in its method of use and production, and even when the drug is an unstable compound in the pressure-sensitive adhesive layer, the drug is prevented from being decomposed and deteriorated during storage. It is an object of the present invention to provide a transdermally absorbable preparation that can be stored stably and can be percutaneously absorbed when the drug is transferred to the adhesive layer and the skin when the preparation is applied.
As a result of intensive studies to solve the above problems, the present inventors have obtained a percutaneous absorption preparation comprising a support, a drug storage layer, a permeation control film, an adhesive layer, and a release material, It has been found that a percutaneously absorbable preparation characterized in that the control membrane is plasticized by moisture that evaporates from the skin when the preparation is applied, and has completed the present invention.
That is, the present invention includes the following inventions.
(1) A percutaneous absorption preparation comprising a support, a drug storage layer, a permeation control film, an adhesive layer, and a release material, wherein the permeation control film is plasticized by moisture that evaporates from the skin when the preparation is applied. A transdermally absorbable preparation characterized by the above.
(2) The percutaneous absorption preparation according to (1), wherein the permeation control membrane is a water-soluble polymer.
(3) The transdermally absorbable preparation according to (2), wherein the water-soluble polymer is polyvinyl alcohol.
(4) The percutaneously absorbable preparation according to (1), wherein the drug storage layer is formed of a drug or a drug and an excipient.
(5) The transdermal preparation according to (4), wherein the drug is water-soluble.
(6) The transdermally absorbable preparation according to (4), wherein the excipient is a water-disintegrating substance.
(7) The percutaneous absorption preparation according to (1), wherein the support has a moisture permeability of 100 g / m 2 or less at 40 ° C. for 24 hours.
(8) The transdermal preparation according to (1), wherein the moisture permeability of the pressure-sensitive adhesive is 100 g / m 2 or more at 40 ° C. for 24 hours.
(9) The percutaneous absorption preparation according to (1), wherein the therapeutic drug is nicorandil, dopamine hydrochloride or eperisone hydrochloride.
Hereinafter, the present invention will be described in detail.
The transdermally absorbable preparation of the present invention is a transdermally absorbable preparation comprising a support, a drug storage layer, a permeation control film, an adhesive layer and a release material, and the permeation control film is removed from the skin when the preparation is applied. It is characterized by being plasticized by the evaporating moisture.
“Plasticization” means “to make a material easy to cause plastic deformation and plastic flow due to external force”. In this case, the permeation control membrane causes plastic flow by absorbing moisture and is activated by moisture. The drug is permeated, dissolved, dispersed or diffused into the permeation control membrane.
In the percutaneous absorption type preparation of the present invention, the permeation control membrane is located between the drug storage layer and the pressure-sensitive adhesive layer and needs to be plasticized by moisture volatilized from the skin when the preparation is applied. Alternatively, the drug and the excipient permeate, dissolve, disperse or diffuse into the permeation control membrane and transfer to the adhesive layer, whereby the drug is absorbed through the skin. The permeation control film is not particularly limited as long as it is plasticized by moisture evaporating from the skin and allows the drug to permeate when the preparation is applied. Examples of such a permeation control membrane include water-soluble polymers, preferably synthetic polymers such as polyvinyl alcohol and polyvinylpyrrolidone, soluble starch, dextrin, cellulose, methylcellulose, carboxymethylcellulose and other polysaccharides, corn starch, sodium alginate, Natural polymers such as gum arabic, gelatin and pullulan, and inorganic polymers such as sodium polyphosphate and water glass, with polyvinyl alcohol being particularly preferred.
In the transdermal preparation of the present invention, the drug storage layer is formed of a drug, or a drug and an excipient.
The excipient is not particularly limited as long as it is generally used, and a water-disintegrating substance is preferably used. The “water-disintegrating substance” as used herein refers to a “substance that functions as an excipient when preparing a drug storage layer and functions as a disintegrant in the presence of moisture when a formulation is applied”. Examples of such water-disintegrating substances include glucose, lactose, sucrose, starch, soluble starch, sugars such as methylcellulose, polyethylene glycols, polysorbates and the like.
The therapeutic drug used in the drug storage layer is not particularly limited as long as it can be absorbed transdermally, but is preferably an amine therapeutic drug such as nicorandil, dopamine hydrochloride or eperisone hydrochloride.
In addition, non-steroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, antiarrhythmic drugs, antitumor drugs, sleeping drugs, psychotropic drugs, local anesthetics, cardiotonic drugs, antibiotics, antituberculosis drugs, analgesia Examples include drugs, muscle relaxants, anti-asthma drugs, anti-cholinergic drugs, vasodilators, anti-hypertensive drugs, antihistamines, cholinergic drugs, angiotensin converting enzyme inhibitors and the like.
The therapeutic drug used in the transdermally absorbable preparation of the present invention needs to permeate, dissolve, disperse, or diffuse into a permeation control membrane plasticized by moisture evaporating from the skin.
In the drug storage layer, additives such as kaolin, talc, bentonite, titanium oxide, calcium hydrogen carbonate, aluminum sulfate, anhydrous silicic acid, zinc oxide, silica, alumina, etc .; BHT, BHA, guaiacol ester, Antioxidants such as nordihydroguaiaretic acid; absorption promoters such as crotamiton, benzyl alcohol, ethanol, diethyl sebacate and isopropyl myristate may be added.
In order to retain the drug storage layer in the transdermally absorbable preparation of the present invention, it is necessary to cover the top or the outside of the drug storage layer with a support.
The support in the percutaneous absorption-type preparation of the present invention is not particularly limited as long as it is drug-impermeable and moisture-impermeable, but the moisture permeability after 40 hours at 40 ° C. (JIS Z0208 “Permeability of moisture-proof packaging material”). According to the “humidity test method (cup method)” is preferably 100 g / m 2 or less. Examples of such a support include films and sheets of polyethylene terephthalate, polyethylene, polypropylene, etc., laminated sheets using two or more of these, and laminated sheets of the film or sheet and nonwoven fabric or woven fabric. It is done.
In the transdermal preparation of the present invention, the adhesive is not particularly limited as long as it can be applied to the skin and is permeable to moisture, but has a moisture permeability of 100 g / m 2 or more after 24 hours at 40 ° C. preferable. Examples of such adhesives include acrylic adhesives, rubber adhesives, and silicone adhesives. In addition to the above-mentioned pressure-sensitive adhesive, the pressure-sensitive adhesive layer can be made of rosin resin, terpene resin, aromatic hydrocarbon resin, aliphatic hydrocarbon resin, petroleum resin, ester gum, oily phenol resin, etc. Giving agents, isopropyl myristate, oleyl oleate, polybutene, isopolybutene, liquid paraffin, squalene, silicone oil, olive oil, soybean oil, rapeseed oil, coconut oil, beef tallow, etc .; kaolin, talc, bentonite, titanium oxide, Additives such as calcium bicarbonate, aluminum sulfate, silicic anhydride, zinc oxide, silica, alumina; antioxidants such as BHT, BHA, guaiacol ester, nordihydroguaiaretic acid; crotamiton, benzyl alcohol, ethanol, sebacic acid Contains absorption aids such as diethyl and isopropyl myristate It may be.
In the transdermal preparation of the present invention, the release material is not particularly limited as long as it is flexible and drug-impermeable, and examples thereof include a film made of polyethylene, polyester, etc. and a silicone resin applied as a release agent. It is done.
As one embodiment of the transdermal preparation of the present invention, one having the structure shown in FIGS. 1 (A) and (B) can be exemplified.
1A and 1B, 1 is a support, 2 is a drug storage layer, 3 is a permeation control film, 4 is an adhesive layer, and 5 is a release material.
In the percutaneous absorption preparation shown in FIG. 1, the
The drug contained in the
This specification includes the contents described in the specification of Japanese Patent Application No. 11-165893, which is the basis of the priority of the present application.
BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described more specifically with reference to the following examples and comparative examples. However, the scope of the present invention is not limited to these examples.
Example 1
4.0 parts by weight of a crosslinking agent (CK-101, manufactured by Nippon Carbide Industries) is added to 100 parts by weight of an acrylic pressure-sensitive adhesive (PE-300, manufactured by Nippon Carbide Industries), and the solid weight% based on the total weight is 40. Ethyl acetate was added so that it might become weight%, and it stirred well with the disper and prepared the uniform solution. This solution was uniformly applied onto a release film made of a polyethylene terephthalate film having a thickness of 38 μm, and dried in a dryer at 80 ° C. for 4 minutes to form an adhesive layer so that the coating amount was 50 g / m 2. Formed. Next, a 25 μm thick polyvinyl alcohol film as a permeation control film was bonded onto the pressure-sensitive adhesive layer.
10 parts by weight of nicorandil was dissolved in 90 parts by weight of methanol to prepare a nicorandil concentration of 10% (w / w). This solution was uniformly applied onto a 50 μm thick polyethylene terephthalate film and dried in a dryer at 60 ° C. for 1 minute to form a drug storage layer so that the content of nicorandil was about 300 mg / m 2 . .
This was pasted with the polyvinyl alcohol film, the pressure-sensitive adhesive layer and the release material prepared earlier to prepare a percutaneous absorption type preparation.
(Example 2)
In the preparation of the drug storage layer of Example 1, the same operation as in Example 1 was performed, except that the amount of nicorandil applied was about 300 mg / m 2 to about 600 mg / m 2. A mold formulation was prepared.
(Example 3)
The drug storage layer of Example 1 was produced as follows. First, 4 parts by weight of soluble starch as an excipient was dissolved in 100 parts by weight of purified water, then 20 parts by weight of nicorandil was added, and 300 parts by weight of ethanol was added thereto and stirred. This solution was uniformly applied on a polyethylene terephthalate film and dried in a dryer at 110 ° C. for 3 minutes to form a drug storage layer. Except for this operation, the same operation as in Example 1 was performed to prepare a transdermal absorption preparation so that the content of nicorandil was about 300 mg / m 2 .
Example 4
The percutaneous absorption preparation is carried out in the same manner as in Example 1 except that eperisone hydrochloride is used instead of nicorandil used in Example 1, so that the content of eperisone hydrochloride is about 300 mg / m 2. Was made.
(Example 5)
The percutaneous absorption preparation is carried out in the same manner as in Example 1 except that dopamine hydrochloride is used instead of nicorandil used in Example 1, so that the content of dopamine hydrochloride is about 300 mg / m 2. Was made.
(Example 6)
The drug storage layer of Example 1 was produced as follows. 20 parts by weight of nicorandil and 80 parts by weight of soluble starch as an excipient were mixed and dispersed, and this was uniformly coated on the permeation control membrane. Except for this operation, the same operation as in Example 1 was performed to prepare a transdermal absorption preparation having a nicorandil content of about 300 mg / m 2 .
(Comparative Example 1)
To 100 parts by weight of the acrylic pressure-sensitive adhesive (PE-300, manufactured by Nippon Carbide Industries), 4.0 parts by weight of a crosslinking agent (CK-101, manufactured by Nippon Carbide Industries), and 0.27 parts by weight of nicorandil are added, Ethyl acetate was added so that the solid weight% with respect to the total weight was 40% by weight, and the mixture was sufficiently stirred with a disper to prepare a uniform solution. This solution was uniformly applied onto a release film made of a polyethylene terephthalate film having a thickness of 38 μm and dried in a dryer at 80 ° C. for 4 minutes. The application amount was 50 g / m 2 and the content of nicorandil was about 300 mg. The pressure-sensitive adhesive layer was formed so as to be / m 2 . Next, a 50 μm thick polyethylene terephthalate film was bonded to prepare a transdermal absorption preparation.
(Comparative Example 2)
The percutaneously absorbable preparation was prepared in the same manner as in Comparative Example 1 except that eperisone hydrochloride was used instead of nicorandil used in Comparative Example 1, so that the content of eperisone hydrochloride was about 300 mg / m 2. Was made.
(Comparative Example 3)
The percutaneously absorbable preparation was prepared in the same manner as in Comparative Example 1 except that dopamine hydrochloride was used instead of nicorandil used in Comparative Example 1, so that the content of dopamine hydrochloride was about 300 mg / m 2. Was made.
(Test Example 1)
The percutaneous absorption preparations having the compositions shown in Table 1 below obtained in Examples 1 to 6 and Comparative Examples 1 to 3 were cut into 25 mm × 150 mm and packaged with aluminum packaging materials. 6 and Comparative Example 1 were stored in a 23 ° C. constant temperature bath (humidity 65%) for 8 weeks, and Examples 4 and 5 and Comparative Examples 2 and 3 were stored in a 40 ° C. constant temperature bath (dry) for 7 days. The amount of drug remaining in the solution was quantified by HPLC. The results of the time stability test are shown in Table 2.
Using the percutaneous absorption preparations obtained in Examples 1 to 3, the transdermal absorbability was evaluated by the following method.
After 8 weeks old (170-190 g body weight) male Wistar rats were sacrificed on the cervix, the abdominal skin was removed by hair removal with a clipper and a shaver. After removing fat on the dermis side with scissors, the percutaneous absorption type preparation obtained in Examples 1 to 3 was applied to the stratum corneum side, and a vertical diffusion cell (cell volume 4.0 ml, maintained at 37 ° C. in advance) An effective diffusion area of 0.95 cm 2 ) was applied, and a permeation experiment was performed by applying a pH 7.4 isotonic phosphate buffer to the dermis side. During the experiment, a star head type stirring bar placed in the dermis side cell was stirred with a magnetic stirrer. A certain amount of sample was collected over time, added to acetonitrile containing an internal standard in advance, and the permeated drug was quantified by HPLC. The cumulative drug permeation amount up to 12 hours after the start of the permeation test is shown in FIG. In FIG. 2, ◯ represents the result of Example 1, □ represents the result of Example 2, and Δ represents the result of Example 3.
All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety.
Industrial Applicability According to the present invention, the method of use and the production method are simple, and the drug is stably stored by suppressing the decomposition and deterioration of the drug during storage, and the drug adheres to the drug when applied to the preparation. It is possible to provide a preparation for transdermal absorption which can be transferred to a pharmaceutical layer and skin and transdermally absorbed.
[Brief description of the drawings]
FIG. 1 is a cross-sectional view of the transdermally absorbable preparation of the present invention.
In addition, the number in a figure shows the following.
DESCRIPTION OF
Claims (5)
前記薬物貯蔵層が薬物のみで形成され、
前記薬物がニコランジル、塩酸ドパミン又は塩酸エペリゾンであり、
前記粘着剤層が薬物を含有せず、前記透過制御膜が水溶性ポリマーからなることを特徴とする経皮吸収型製剤。A percutaneously absorbable preparation comprising a support, a drug storage layer, a permeation control film, an adhesive layer and a release material,
The drug storage layer is formed only of a drug;
The drug is nicorandil, dopamine hydrochloride or eperisone hydrochloride;
The transdermal preparation, wherein the pressure-sensitive adhesive layer does not contain a drug, and the permeation control film is made of a water-soluble polymer.
前記薬物貯蔵層が薬物及び賦形剤のみで形成され、The drug reservoir layer is formed of only drugs and excipients;
前記賦形剤がブドウ糖、乳糖、蔗糖、デンプン及び可溶性デンプンから選ばれる糖類であり、The excipient is a saccharide selected from glucose, lactose, sucrose, starch and soluble starch;
前記薬物がニコランジル、塩酸ドパミン又は塩酸エペリゾンであり、The drug is nicorandil, dopamine hydrochloride or eperisone hydrochloride;
前記粘着剤層が薬物を含有せず、前記透過制御膜が水溶性ポリマーからなることを特徴とする経皮吸収型製剤。The transdermal preparation, wherein the pressure-sensitive adhesive layer does not contain a drug, and the permeation control film is made of a water-soluble polymer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2001502819A JP4889172B2 (en) | 1999-06-11 | 2000-06-09 | Moisture sensitive transdermal formulation |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11-165693 | 1999-06-11 | ||
| JP16569399 | 1999-06-11 | ||
| JP1999165693 | 1999-06-11 | ||
| JP2001502819A JP4889172B2 (en) | 1999-06-11 | 2000-06-09 | Moisture sensitive transdermal formulation |
| PCT/JP2000/003782 WO2000076485A1 (en) | 1999-06-11 | 2000-06-09 | Moisture-sensitive preparation of percutaneous absorption type |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPWO2000076485A1 JPWO2000076485A1 (en) | 2003-01-07 |
| JP4889172B2 true JP4889172B2 (en) | 2012-03-07 |
Family
ID=15817261
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2001502819A Expired - Fee Related JP4889172B2 (en) | 1999-06-11 | 2000-06-09 | Moisture sensitive transdermal formulation |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US6733785B1 (en) |
| JP (1) | JP4889172B2 (en) |
| WO (1) | WO2000076485A1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10159745A1 (en) * | 2001-12-05 | 2003-07-03 | Lohmann Therapie Syst Lts | Transdermal therapeutic system with improved long-term comfort |
| JP4557596B2 (en) * | 2004-04-28 | 2010-10-06 | 積水化成品工業株式会社 | External patch, method for producing the same, and method for using the same |
| FR2894465B1 (en) * | 2005-12-14 | 2010-09-10 | Fabre Pierre Dermo Cosmetique | USE OF POLYUNSATURATED COMPOUNDS AS BLANCHING AGENTS |
| WO2008112227A1 (en) * | 2007-03-12 | 2008-09-18 | Reliant Pharmaceuticals, Inc. | Treatment with nicorandil and omega-3 fatty acids, and a combination product thereof |
| WO2010073326A1 (en) * | 2008-12-24 | 2010-07-01 | ニチバン株式会社 | Percutaneous absorption preparation |
| CN104582693A (en) * | 2012-08-15 | 2015-04-29 | 道康宁公司 | Multi-layer transdermal drug delivery system |
| JPWO2018199018A1 (en) * | 2017-04-26 | 2020-03-12 | ニプロ株式会社 | Transdermal preparation and method for producing the same |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3598122A (en) * | 1969-04-01 | 1971-08-10 | Alza Corp | Bandage for administering drugs |
| JPS62221620A (en) * | 1986-03-12 | 1987-09-29 | メルク エンド カムパニ− インコ−ポレ−テツド | Percutaneous drug delivery system |
| JPS63203616A (en) * | 1987-02-18 | 1988-08-23 | Hisamitsu Pharmaceut Co Inc | Clonidine percutaneous administration matrix |
| JPH02149514A (en) * | 1988-04-06 | 1990-06-08 | Nitto Denko Corp | Material for medicine |
| JPH041125A (en) * | 1990-04-17 | 1992-01-06 | Nitto Denko Corp | Multistage drug-releasable percutaneous pharmaceutical |
| JPH041127A (en) * | 1990-04-18 | 1992-01-06 | Nitto Denko Corp | Plaster for medical treatment |
| JPH09143062A (en) * | 1995-11-21 | 1997-06-03 | Mikasa Seiyaku Kk | Tacky agent composition for percutaneous application and its production |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NO134790C (en) * | 1968-07-09 | 1984-03-22 | Smith & Nephew | Kleber ,; PRESSURE SENSITIVE, WATERPUME-PERMEABLE PRODUCT FOR SKIN USE BY HUMANS. |
| JPH0627068B2 (en) | 1984-09-22 | 1994-04-13 | 中外製薬株式会社 | Transdermal drug |
| US5446070A (en) * | 1991-02-27 | 1995-08-29 | Nover Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
| US5232702A (en) * | 1991-07-22 | 1993-08-03 | Dow Corning Corporation | Silicone pressure sensitive adhesive compositons for transdermal drug delivery devices and related medical devices |
| CA2075517C (en) * | 1992-04-01 | 1997-03-11 | John Wick | Transdermal patch incorporating a polymer film incorporated with an active agent |
-
2000
- 2000-06-09 US US09/762,615 patent/US6733785B1/en not_active Expired - Fee Related
- 2000-06-09 JP JP2001502819A patent/JP4889172B2/en not_active Expired - Fee Related
- 2000-06-09 WO PCT/JP2000/003782 patent/WO2000076485A1/en not_active Ceased
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3598122A (en) * | 1969-04-01 | 1971-08-10 | Alza Corp | Bandage for administering drugs |
| US3598122B1 (en) * | 1969-04-01 | 1982-11-23 | ||
| JPS62221620A (en) * | 1986-03-12 | 1987-09-29 | メルク エンド カムパニ− インコ−ポレ−テツド | Percutaneous drug delivery system |
| JPS63203616A (en) * | 1987-02-18 | 1988-08-23 | Hisamitsu Pharmaceut Co Inc | Clonidine percutaneous administration matrix |
| JPH02149514A (en) * | 1988-04-06 | 1990-06-08 | Nitto Denko Corp | Material for medicine |
| JPH041125A (en) * | 1990-04-17 | 1992-01-06 | Nitto Denko Corp | Multistage drug-releasable percutaneous pharmaceutical |
| JPH041127A (en) * | 1990-04-18 | 1992-01-06 | Nitto Denko Corp | Plaster for medical treatment |
| JPH09143062A (en) * | 1995-11-21 | 1997-06-03 | Mikasa Seiyaku Kk | Tacky agent composition for percutaneous application and its production |
Also Published As
| Publication number | Publication date |
|---|---|
| US6733785B1 (en) | 2004-05-11 |
| WO2000076485A1 (en) | 2000-12-21 |
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